Process for producing microsphere

Abstract

A process for producing microspheres, which comprises adding a polymer solution containing a medicament, a biodegradable polymer and a good solvent for said polymer which solvent is miscible with water (Solvent A) to a homogeneous mixture of a poor solvent for said polymer which solvent is miscible with said Solvent A (Solvent B) and a poor solvent for said polymer which solvent is immiscible with said Solvent A (Solvent C), emulsifying the mixture to prepare an emulsion wherein the polymer solution forms a dispersed phase and the homogeneous mixture forms a continuous phase, and then removing Solvent A from the dispersed phase.

1 . A process for producing microspheres, which comprises adding a polymer solution containing a medicament, a biodegradable polymer and a good solvent for said polymer which solvent is miscible with water (Solvent A) to a homogeneous mixture of a poor solvent for said polymer which solvent is miscible with said Solvent A (Solvent B) and a poor solvent for said polymer which solvent is immiscible with said Solvent A (Solvent C), emulsifying the mixture to prepare an emulsion wherein the polymer solution forms a dispersed phase and the homogeneous mixture forms a continuous phase, and then removing Solvent A from the dispersed phase.  
     
     
         2 . The process according to  claim 1 , wherein the biodegradable polymer is a polyester of a hydroxyfatty acid.  
     
     
         3 . The process according to  claim 1 , wherein the biodegradable polymer is one or more members selected from polylactic acid, a copolymer of lactic acid—glycolic acid, and a copolymer of 2-hydroxybutyric acid—glycolic acid.  
     
     
         4 . The process according to any one of  claims 1  to  3 , wherein Solvent A is one or more members of the solvents selected from a group consisting of acetone, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, dioxane, diglyme and ethyleneglycol dimethyl ether, Solvent B is one or more members of the solvents selected from the group consisting of water and a monovalent alcohol having 1 to 4 carbon atoms, and Solvent C is glycerine.  
     
     
         5  The process according to  claim 4 , wherein the monovalent alcohol having 1 to 4 carbon atoms is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol.  
     
     
         6 . The process according to  claim 4 , wherein Solvent A is acetone, Solvent B is water, and Solvent C is glycerine.  
     
     
         7 . The process according to any one of  claims 1  to  6 , wherein the ratio of Solvent B and Solvent C in the homogeneous mixture is in the range of 5:95 to 75:25 by weight.  
     
     
         8 . The process according to any one of  claims 1  to  7 , wherein the amount of Solvent A is not more than the maximum amount of Solvent A being miscible with the homogenous mixture of Solvent B and Solvent C.  
     
     
         9 . The process according to any one of  claims 1  to  8 , wherein the polymer solution contains Solvent B.  
     
     
         10 . The process according to  claim 9 , wherein the polymer solution has a content of Solvent B in the range of 0.001 to 50% by weight.  
     
     
         11 . The process according to any one of  claims 1  to  10 , wherein the homogeneous mixture contains an emulsion stabilizer.  
     
     
         12 . The process according to any one of  claims 1  to  11 , wherein the homogeneous mixture contains Solvent A.  
     
     
         13 . The process according to  claim 12 , where the emulsification procedure is carried out below 0° C.  
     
     
         14 . The process according to any one of  claims 1  to  13 , wherein the ratio of the polymer solution and the homogeneous mixture is in the range of 1:1 to 1:1000 by weight.  
     
     
         15 . The process according to any one of  claims 1  to  14 , wherein after emulsifying the amount of the continuous phase is increased by mixing the resulting emulsion and a separately prepared increasing solvent, and Solvent A is removed.  
     
     
         16 . The process according to  claim 15 , wherein the increasing solvent is Solvent B or a mixture of Solvent B and Solvent C.  
     
     
         17 . The process according to  claim 16 , wherein Solvent B used as the increasing solvent is one or more solvents selected from water and a monovalent alcohol having 1 to 4 carbon atoms, and Solvent C used as the increasing solvent is glycerine.  
     
     
         18 . The process according to  claim 16 , wherein Solvent B used as the increasing solvent is a monovalent alcohol having 1 to 4 carbon atoms, and the removal of Solvent A is carried out below 0° C.  
     
     
         19 . The process according to any one of  claims 15  to  18 , wherein the ratio of Solvent B in the continuous phase of the emulsion after increasing thereof is the same as or larger than the ratio of Solvent B before increasing.  
     
     
         20 . The process according to any one of  claims 15  to  19 , wherein the continuous phase after increasing thereof has a volume of 2 to 100 times larger than that before increasing.  
     
     
         21 . The process according to any one of  claims 1  to  12 ,  14  to  17 ,  19  and  20 , wherein the removal of Solvent A is carried out by warming the emulsion.  
     
     
         22 . The process according to  claim 21 , wherein the warming is carried out at a temperature of 30 to 70° C.  
     
     
         23 . The process according to any one of  claims 1  to  22 , wherein the removal of Solvent A is carried out by placing the emulsion under reduced pressure after emulsifying step.  
     
     
         24 . The process according to  claim 23 , wherein the pressure after reduced pressure is in the range of 5 to 80 kPa.  
     
     
         25 . The process according to any one of  claims 1  to  24 , wherein the removal of Solvent A is carried out in a closed system.  
     
     
         26 . A process for removing Solvent A remained in the microspheres prepared by the process as set forth in one of  claims 1  to  25 , which comprising re-dispersing said microspheres in water, and stirring the resulting mixture.